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The Use of Direct Acting Oral Anti-Coagulants in Vulnerable Populations

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Introduction

Direct oral anticoagulants (DOACs) are a class of oral anticoagulants developed as a more reliable option than warfarin. Since 2010, four DOACs have been approved by the United States (US) Food and Drug Administration (FDA) for the treatment of non-valvular atrial fibrillation (Afib) and venous thromboembolism (VTE) including dabigatran, rivaroxaban, apixaban, and edoxaban.1 The mechanism of this class is different than warfarin, and involves a direct antagonism of clotting factors IIa (dabigatran) or Xa (rivaroxaban, apixaban, and edoxaban). The DOACs are equally or more effective than warfarin in preventing a stroke from Afib or recurrent VTE and have several advantages over warfarin including an improved safety profile, the absence of routine monitoring requirements, few significant drug-drug interactions, and almost no dietary restrictions. Due to these benefits, many guidelines (see Resources) recommend DOAC over warfarin use in most patients with an indication for anticoagulation, and as of 2017, DOACs accounted for about 80% of new oral anticoagulant prescriptions in patients with Afib and VTE.2,3

Despite the benefits of this class of medications compared to warfarin, variability still exists in the quality of data in vulnerable populations such as those with renal impairment, obesity, older adults, cancer, or patients with a hypercoagulable state. Though guidance in some of these populations has been updated to include DOACs, individual guidance for each patient must be determined based on patient specific factors. Additionally, racial and ethnic minorities were underrepresented in significant trials, and more research is needed to understand how treatment effects and toxicities may be different in these patients. Therefore, outcomes in primarily Caucasian populations may not necessarily be extrapolated to non-Caucasian patients.

As key members of the healthcare team, pharmacists can advise other members of the care team on selection of a DOAC that is appropriate for an individual patient, including a specific dose and duration.

This activity provides an overview of current best practices for using DOACs in vulnerable populations and discusses the questions that pharmacists are most often called upon to answer with respect to DOAC use in these patients.

DOACs Approved in the United States

Though the DOACs have many similarities among the class, the differences are what allow healthcare providers to select the most appropriate agent for a specific patient. Selecting appropriate dosages, assessing drug-drug interactions, and adherence can be additional barriers to appropriate use. Table 1 summarizes pharmacokinetic (PK) and pharmacodynamic (PD) parameters, dose adjustments, and other important information for each agent.

Table 1. Profiles of FDA-approved DOACs.

Dabigatran4
 Rivaroxaban5
 Apixaban6
  Edoxaban7
Pharmacokinetic and Pharmacodynamic Parameters
Mechanism of Action IIa inhibitor Xa inhibitor Xa inhibitor Xa inhibitor
Pro-Drug Yes No No No
Half-Life 8-15 hours 7-11 hours 12 hours 10-14 hours
Bioavailability 6% 60-80% 60% 62%
Renal Clearance 80% 33% 25% 50%
Metabolism P-gp efflux transporter P-gp efflux transporter and CYP3A4 enzyme P-gp efflux transporter and CYP3A4 enzyme P-gp efflux transporter
Dose and Dose Adjustments
Non-valvular Afib 150 mg twice daily 20 mg once daily with food 5 mg twice daily 60 mg once daily
Non-valvular Afib Dose Adjustments

CrCl 30-50 mL/min + dronedarone or systemic ketoconazole: 75 mg twice daily

CrCl 15-30 mL/min: 75 mg twice daily

CrCl <15 mL/min: avoid use

CrCl ≤50 mL/min: 15 mg once daily with food

2.5 mg twice daily if two of the following 3 criteria are met:

- ≥80 years old

- ≤60 kg

- SCr ≥1.5 mg/dL

Avoid if CrCl >95 mL/min or <15 mL/min

CrCl 15-50 mL/min: 30 mg once daily
DVT/PE Treatment

150 mg twice daily after 5-10 days of parenteral anticoagulant

 15 mg twice daily x 21 days, then 20 mg daily with food 10 mg twice daily x 7 days, then 5 mg twice daily 60 mg once daily after 5-10 days of parenteral anticoagulant
DVT/PE Treatment Dose Adjustments

CrCl <50 mL/min + P-gp inhibitor use: avoid

CrCl <30 mL/min or dialysis: avoid use

 CrCl <30 mL/min: avoid None 30 mg once daily if CrCl 15-50 mL/min or ≤60 kg or P-gp inhibitors
Notes

Must be stored in original packaging
 For doses >10 mg, must be administered with food

Afib, atrial fibrillation; CrCl, creatinine clearance; DVT, deep vein thrombosis; PE, pulmonary embolism; SCr, serum creatinine

Atrial Fibrillation

Anticoagulation is recommended in patients with Afib to decrease the risk of stroke. Dabigatran, rivaroxaban, apixaban, and edoxaban have all been FDA-approved for treatment of Afib based on landmark trials showing similar or superior safety and efficacy compared to warfarin, which are summarized in Table 2. The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) with Dabigatran Etexilate trial assessed over 18,000 patients with Afib randomized to dabigatran or warfarin.8 Results determined that dabigatran had a lower risk of stroke and systemic embolism, and a similar risk of major hemorrhage compared to warfarin. Rivaroxaban was compared to warfarin in patients with Afib in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).9 This trial demonstrated noninferiority in risk of stroke, and similar bleeding outcomes between both groups. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial assessed apixaban compared to warfarin.10 In this trial, apixaban showed a lower rate of stroke and systemic embolism, bleeding, and mortality compared to warfarin. The Global Study to Assess the Safety and Effectiveness of Edoxaban vs Standard Practice of Dosing with Warfarin in Patients With Atrial Fibrillation (Engage-AF TIMI 48) trial compared edoxaban and warfarin in patients with Afib.11 Results showed noninferiority compared to warfarin for stroke and systemic embolism and a lower rate of bleeding and death from cardiovascular (CV) causes.

Practice Point

Based on the results of large randomized trials, guidelines (see Resources) for treatment of Afib recommend the use of DOACs over warfarin in most patients.8-11 No landmark trials have been completed that compare DOACs to each other in patients with Afib, and thus comparative efficacy and safety is undetermined within the class.
Table 2. Landmark trial summaries for DOAC use in Afib.
Trial Treatment Groups Efficacy Outcome, n (%)
 Safety Outcome, n (%)

RE-LY8

n=18,113

 Dabigatran 150 mg twice daily versus warfarin INR 2-3

Stroke/systemic embolism

Dabigatran: 134 (1.11%/yr)

Warfarin: 199 (1.69%/yr)

RR: 0.66, 95% CI 0.53-0.82

Major bleeding

Warfarin: 397 (3.36%/yr)
Dabigatran: 375 (3.11%/yr)

RR: 0.93, 95% CI 0.81-1.07

ROCKET-AF9

n=14,264

 Rivaroxaban 20 mg daily versus warfarin INR 2-3

Stroke/systemic embolism

Rivaroxaban: 188 (1.7%/yr)

Warfarin: 241 (2.2%/yr)

HR: 0.79, 95% CI 0.66-0.96

Major or CRNMB

Rivaroxaban: 1475 (14.9%/yr)

Warfarin: 1449 (14.5%/yr)

HR: 1.03, 95% CI 0.96-1.11

ARISTOTLE10

n=18,201

 Apixaban 5 mg twice daily versus warfarin INR 2-3

Stroke/systemic embolism

Apixaban: 212 (1.27%/yr)

Warfarin: 265 (1.60%/yr)

HR: 0.79, 95% CI 0.66-0.95

Major bleeding

Apixaban: 327 (2.13%/yr)

Warfarin: 462 (3.09%/yr)

HR: 0.69, 95% CI 0.60-0.80

ENGAGE-AF TIMI 4811

n=21,105

 Edoxaban 60 mg daily versus warfarin INR 2-3

Stroke/systemic embolism

Edoxaban: 182 (1.18%/yr)

Warfarin: 232 (1.50%/yr)

HR: 0.79, 97.5% CI 0.63-0.99

Major bleeding

Edoxaban: 418 (2.75%/yr)

Warfarin: 524 (3.43%/yr)

HR: 0.80, 95% CI 0.71-0.91
Afib, atrial fibrillation; CI, confidence interval; CRNMB, clinically relevant non-major bleeding; DOAC, direct oral anticoagulant; HR; hazard ratio; INR, international normalized ratio; RR, risk ratio; yr, year

Venous Thromboembolism (Deep Vein Thrombosis and Pulmonary Embolism)

Anticoagulation is recommended for treatment of VTE including both DVT and PE. The four DOACs have been compared to warfarin in large, randomized clinical trials (RCT), which are summarized in Table 3. Dabigatran has been compared to warfarin in the Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism (RECOVER-I) trial and dabigatran was determined to be non-inferior in terms of recurrent VTE, and bleeding was similar in both treatment groups.12 Rivaroxaban has been studied separately in patients with VTE and PE, however, a pooled analysis of the EINSTEIN studies showed non-inferiority for recurrent VTE, but with an improved safety profile in regards to bleeding.13 Similarly, the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial also showed non-inferiority for recurrent VTE, and an improved bleeding profile.14 Lastly, edoxaban has been studied in the Hokusai-VTE trial, and been determined to be non-inferior for recurrent VTE, and superior in terms of bleeding events.15

Practice Point

Based on the results of large randomized trials, guidelines (see Resources) for treatment of VTE recommend the use of DOACs over warfarin in most patients with or at risk for VTE.12-15 Similar to Afib, comparative RCTs have not been conducted comparing the DOACs, making direct comparisons difficult.

Table 3. Landmark trial summaries for DOAC use in VTE.
Trial Treatment Groups Efficacy Outcome, n (%)
 Safety Outcome, n (%)

RE-COVER I12

n=2,539

 Dabigatran 150 mg twice daily + parenteral bridge vs warfarin INR 2-3 + parenteral bridge

Recurrent VTE

Dabigatran: 30 (2.4%)

Warfarin: 27 (2.1%)

HR: 1.10, 95% CI 0.65-1.84

Major bleeding

Dabigatran: 20 (1.6%)

Warfarin: 24 (1.9%)

HR: 0.82, 95% CI 0.45-1.48

EINSTEIN DVT + EINSTEIN PE POOLED13

n=8,281

 Rivaroxaban 15 mg twice daily x 21 days, then 20 mg daily versus warfarin INR 2-3 + parenteral bridge

Suspected recurrent VTE

Rivaroxaban: 86 (2.1%)

Warfarin: 95 (2.3%)

HR: 0.89, 95% CI 0.66-1.19

Clinically relevant bleeding

Rivaroxaban: 40 (1.0%)

Warfarin: 72 (1.7%)

HR: 0.54, 95% CI 0.37-0.79

AMPLIFY14

n=5,395

 Apixaban 10 mg twice daily x 7 days, then 5 mg twice daily vs warfarin INR 2-3 + parenteral bridge

Recurrent symptomatic VTE or VTE death

Apixaban: 59 (2.3%)

Warfarin: 71 (2.7%)

RR: 0.84, 95% CI 0.60-1.18

Bleeding

Apixaban: 15 (0.6%)

Warfarin: 49 (1.8%)

RR: 0.31, 95% CI 0.17-0.55

Hokusai- VTE15

 Edoxaban 30 or 60 mg daily + parenteral bridge vs warfarin INR 2-3 + parenteral bridge

Recurrent symptomatic VTE

Edoxaban: 130 (3.2%)

Warfarin: 146 (3.5%)

HR: 0.89, 95% CI 0.70-1.13

Major bleeding or CRNMB

Edoxaban: 349 (8.5%)

Warfarin: 423 (10.3%)

HR: 0.81, 95% CI 0.71-0.94
CI, confidence interval; CRNMB, clinically relevant non-major bleeding; DOAC, direct oral anticoagulant; HR; hazard ratio; INR, international normalized ratio; RR, risk ratio; VTE, venous thromboembolism

DOAC Use in Vulnerable Populations

Renal Impairment

Patients with chronic kidney disease (CKD) are at a high risk of bleeding, up to 1.5-fold higher than those without CKD.16,17 This becomes even more concerning in patients with Afib or VTE, as they will likely require treatment with anticoagulation, which further increases their risk of bleeding. The DOACs each undergo a component of renal elimination, suggesting that patients may be exposed to more drug as their renal function declines. In a study assessing a large administrative database in the US (n=14,865), it was determined that of those on a DOAC who met the criteria for renal dose adjustments, 43% were not adjusted correctly, and this increased their risk of bleeding (hazard ratio [HR] 2.19, 95% confidence interval [CI] 1.07-4.46).18 Beyond this, two large analyses of DOAC use in patients with renal impairment show that DOACs have a lower risk of intracranial, but higher risk of gastrointestinal bleeding compared to warfarin.19,20

Practice Point

Specific bleeding risks vary depending on which DOAC the patient is using, the degree of renal dysfunction, and the dose of the DOAC. This calls upon the pharmacist to assess patient and drug specific factors to select the safest medication for patients with renal dysfunction.

Dabigatran

Dabigatran is approximately 80% renally eliminated, suggesting that as renal function declines, a dose adjustment or avoidance of the drug might be necessary to avoid the increased exposure and potential risk of bleeding with this agent.4 The landmark trials for approval included patients down to a creatinine clearance (CrCl) of 30 mL/min, and assessed outcomes in patients with moderate renal dysfunction (CrCl 30-50 mL/min; n=3,374). The results from the post-hoc analysis of RE-LY using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) calculation, determined that dabigatran 150 mg twice daily group showed reduced risk of ischemic/hemorrhagic stroke or systemic embolism (SE) by 1.21% per year in comparison to warfarin at 2.17% per year in patients with a CrCl between 30 and 50 mL/min (HR 0.55, 95% CI 0.34-0.89)21 No significant difference was seen in rates of major bleeding (HR 1.22, 95% CI 0.95-1.58), though in patients with a CrCl between 30 and 50 mL/min, dabigatran 150 mg twice daily had a lower risk of intracranial bleeding than warfarin (HR 0.38, 95% CI 0.16-0.92).21 Results were similar when utilizing the Cockcroft-Gault (CG) equation as well. A post-hoc analysis of RECOVER and RECOVER-II, assessing dabigatran in patients with VTE, similarly excluded patients with a CrCl less than 30 mL/min.22 The primary outcome of recurrent VTE or VTE-related death in patients with a CrCl between 30 and 50 mL/min (n=237) was lower in dabigatran treated patients (0.0%) versus warfarin (4.1%) (HR 0.75, 95% CI 0.31-1.84). Bleeding rates increased as renal function declined, however, there were no differences between treatment groups.

Patients with end stage renal disease (ESRD) receiving dabigatran have also been studied. An analysis of the Fresenius Medical Care North America (FMCNA) ESRD database sought to determine the prevalence of dabigatran or rivaroxaban use for any indication in patients receiving hemodialysis as well as rates of bleeding or arterial embolism.23 This study included 281 patients receiving dabigatran and 8,064 receiving warfarin and found no statistically significant difference in rates of embolic stroke and arterial embolism in these patients, though event rates were low. However, higher rates of bleeding were seen in those receiving dabigatran compared to warfarin (HR 2.59, 95% CI 1.89-3.54) and more hemorrhagic deaths occurred in the dabigatran group (19.2/100 patient years) compared to warfarin (10.2/100 patient years). It is important to note that the study had short follow-up times of less than a year.

Practice Points

These results suggest dabigatran may still be safe in patients with moderate renal dysfunction.21-22 Based on this information, use of dabigatran in patients receiving hemodialysis is not recommended.

For Afib treatment, there are no recommended adjustments for a CrCl greater than 30 mL/min; however, with a CrCl of 15-29 mL/min a dose adjustment is recommended based solely on pharmacokinetic modeling data.24-26

For VTE, no dose adjustments are required in those with a CrCl more than 30 mL/min, and should be avoided with a CrCl less than 30 mL/min due to an exclusion of these patients from the clinical trials.

These dose adjustments may require further changes based on numerous drug interactions that exist with dabigatran. For practical purposes, selection of other DOACs in renal impairment may be a simpler solution.

Rivaroxaban

About two-thirds of rivaroxaban is renally eliminated (half as unchanged drug, half as metabolite), and thus it is expected that renal dose adjustments may be necessary for this medication.5 In the landmark trials assessing rivaroxaban for Afib or VTE, patients with a CrCl <30 mL/min were excluded. Both assessed patients with moderate renal impairment, CrCl of 30-49mL/min, and ROCKET-AF showed no difference in ischemic (HR 0.84, 95% CI 0.57-1.23) or hemorrhagic stroke or SE (HR 0.56, 95% CI 0.21-1.51) between rivaroxaban and warfarin in Afib.27 Similar results were shown in the subpopulation of Japanese patients.28 Furthermore, there was no significant difference seen in major bleeding and the composite of major bleeding and non-major, clinically relevant bleeding between agents.27 The EINSTEIN DVT and PE studies similarly excluded patients with a CrCl less than 30 mL/min and found no difference seen in recurrent VTE or bleeding events.29,30

In the previously discussed FMCNA trial assessing dabigatran in patients on hemodialysis, 244 patients receiving rivaroxaban were studied.23 No difference in rates of embolic stroke or arterial embolism were observed compared to warfarin, but rivaroxaban did have a higher rate of major (risk ratio [RR] 1.45, 95% CI 1.09–1.93) and minor bleeding (RR 1.36, 95% CI 1.12–1.64). This resulted in a higher rate of mortality due to bleeding in the rivaroxaban group at 16.2 deaths per 100 patient-years versus 10.2 deaths per 100 patient-years in the warfarin group, but the statistical significance of this outcome was not reported.

Practice Points

Based on this information, the risk of bleeding outweighs the benefit of rivaroxaban use in patients receiving hemodialysis, and it is not recommended.

For Afib treatment, rivaroxaban should be avoided in those with a CrCl <15 mL/min and dose adjusted to 15 mg daily with a CrCl 15-50 mL/min, though it is important to note that those in the CrCl range of 15-29 mL/min were not included in the RCT. This recommendation comes from a single dose pharmacokinetic study using rivaroxaban 10 mg once daily, which did not assess clinical outcomes.31

For VTE, use should also be avoided in patients with a CrCl less than 15 mL/min, but above this, dose adjustment is not necessary.5 It is again important to note that the studies excluded patients with a CrCl of 15-29 mL/min, and the exposure to the drug may increase in this population.

Apixaban

In contrast to the other DOACs, only about a quarter of apixaban is renally excreted.6 Though this still warrants consideration and possible dose adjustments, the impact on medication exposure to the patient is minimal compared to the other DOACs. In the landmark trial for apixaban use in Afib, ARISTOTLE, patients with a serum creatinine (SCr) greater than 2.5 mg/dL or a CrCl less than 25 mL/min were excluded. However, a post-hoc analysis of this trial assessed outcomes based on renal function using the CG as well as the CKD-EPI equations. In patients with moderate CKD per the CG method (CrCl 25-50 mL/min), results determined no significant difference in stroke or SE with apixaban compared to warfarin (RR 0.79, 95% CI 0.55-1.14), and with the CKD-EPI estimation (estimated glomerular filtration rate [eGFR] 25-50 mL/min), a significantly reduced stroke or SE with apixaban compared to warfarin (RR 0.61, 95% CI 0.39-0.94)32 Furthermore, apixaban demonstrated a lower incidence of major bleeding versus warfarin in patients with moderate renal dysfunction with the CG estimation (HR 0.50, 95% CI 0.38-0.66) and the CKD-EPI estimation (HR 0.48, 95% CI 0.37-0.64). Renal exclusion criteria for the landmark trial assessing apixaban in VTE, AMPLIFY, were the same as ARISTOTLE.14 Results of a subgroup analysis determined no efficacy (recurrent VTE or VTE death, p=0.8757) or safety difference (major bleeding, p=0.3606) in those with moderate to severe renal impairment.

Multiple real-world studies have been completed to evaluate apixaban in patients with more severe renal impairment than were included in the landmark trials.33-35 One retrospective matched cohort-study included 146 patients and compared apixaban to warfarin in patients with a SCr less than 2.5 mg/dL or CrCl less than 25 mL/min, including patients receiving dialysis.33 Those receiving apixaban had a lower, but non-significant, incidence of major bleeding (9.6% vs. 17.8%, p=0.149) and no difference in stroke or VTE. A multicenter, retrospective chart review was conducted to evaluate the safety and effectiveness of apixaban compared with warfarin in patients with a CrCl less than 25 mL/min (n=861).35 The apixaban group had a lower incidence of bleeding and thrombotic events compared to warfarin (HR 0.47, 95% CI 0.25-0.92); however, no difference was shown when looking at each outcome individually. A large retrospective cohort (n=25,523) of Medicare beneficiaries in the United States Renal Data System were evaluated among patients with ESRD with a CrCl less than 15 mL/min receiving dialysis on apixaban or warfarin for Afib.34 Cohorts were matched and determined that there was no difference in stroke or SE between apixaban and warfarin (HR 0.88, 95% CI 0.69-1.12), but there was a lower rate of major bleeding (HR 0.72, 95% CI 0.59-0.87).34 Interestingly, a sensitivity analysis assessed apixaban dosing and determined that standard dose (5 mg twice daily) resulted in significantly less stroke or systemic embolism (HR 0.64, 95% CI 0.42-0.97) compared to warfarin and still maintained lower major bleeding rates (HR 0.71, 95% CI 0.53-0.95), while the reduced dosing did not show the decreased rate of systemic embolism.34 This suggests dose reduction should only be completed in patients receiving dialysis if they meet at least one other requirement for a dose adjustment.

Practice Point

These data support the use of apixaban in patients with renal impairment, ESRD, and dialysis.

For Afib, a dose adjustment from 5 mg twice daily to 2.5 mg twice should be completed if two of the following three parameters are met: greater than or equal to 80 years of age, less than or equal to 60 kg, and SCr greater than or equal to 1.5 mg/dL. Of note, dialysis only counts as one parameter (SCr greater than or equal to 1.5 mg/dL), and thus, the dose should not be adjusted for the sole indication of dialysis. For VTE, the manufacturer does not recommend any dose adjustments.6,33,34

Data for use in VTE with ESRD is limited, and alternatives should be considered before treating with apixaban.

Edoxaban

Edoxaban undergoes about 50% renal elimination suggesting that renal function needs to be taken into account when dosing this medication.7 Interestingly, edoxaban loses efficacy at higher creatinine clearances, and thus only has recommended dosing in patients with a CrCl between 30 and 95 mL/min, limiting its utility in patients with good and poor renal function. As with the other DOACs, the landmark trials assessing edoxaban excluded those with severely impaired renal function (CrCl less than 30 mL/min). A post-hoc analysis of the ENGAGE-AF TIMI 48 trial assessing edoxaban for Afib found no difference in stroke or SE between edoxaban and warfarin (HR 0.87, 95% CI 0.65-1.18) and a lower incidence of major bleeding (HR 0.76, 0.58-0.98) in the patients with a CrCl of 30-50 mL/min.36 Additionally, a post-hoc analysis of HOKUSAI-VTE examined edoxaban for VTE, and determined that using the dose-adjusted edoxaban in patients with a CrCl between 30 and 50 mL/hr maintained efficacy, and demonstrated superior safety compared to warfarin.37

Practice Point

These data support the use of edoxaban for Afib or VTE in patients with a CrCl between 30 and 95 mL/min, requiring a dose adjustment from 60 to 30 mg daily in those with a CrCl less than 50 mL/min.36,37 It is again important to note the exclusion of patients with a CrCl less than 30 mL/min, suggesting caution be used in this population due to paucity of data.

Summary of DOAC Use in Renal Impairment

Most data for DOAC use in patients with renal impairment are in patients with moderate renal impairment, with only a few studies with clinical outcomes in patients with ESRD. It is important to note the disparity of information between Afib and VTE, with most data existing for stroke prevention in Afib, making extrapolation to VTE treatment difficult. All DOACs have demonstrated efficacy and safety down to a CrCl of 30 mL/min, though some may require dose adjustments for specific indications with a CrCl less than 50 mL/min (rivaroxaban, edoxaban). For those with severe renal impairment or ESRD (with or without dialysis), a majority of data lies with apixaban which has demonstrated positive outcomes in this scenario. It is important to recall that dose adjustments should only be made for the Afib indication, and only if two of three required criteria are met.

Case 1

NC is a 68-year-old woman who presents to her primary care office with new onset shortness of breath, fatigue, and palpitations. She is diagnosed with new onset paroxysmal atrial fibrillation.

Medical History: Gout, hypertension, depression, CKD (CrCl 17 mL/min)

Medications: Amlodipine 5 mg daily, allopurinol 100 mg daily, sertraline 25 mg daily, dapagliflozin 10 mg daily

Pause and Reflect: What DOAC should be initiated for stroke prevention in NC?

Obesity

Obesity can theoretically increase the risk of clotting due to decreased mobility, venous stasis, and increased inflammatory markers. Curiously, data suggest that patients who are obese may have demonstrated a protective mechanism in some disease states; this is known at the obesity paradox.38,39 In the case of Afib and VTE, it has been shown that those with a higher body mass index (BMI) do have a reduced risk of mortality compared to those with a lower BMI. 38,39 Despite the obesity paradox, patients should still be treated with anticoagulation for appropriate indications. This poses a challenge as the DOACs have different lipophilicity, protein binding, and volume of distribution which may alter a patient’s exposure to the drugs based on their BMI. 

Dabigatran

Dabigatran has a larger volume of distribution in the DOAC class at 0.7-1.0 L/kg, and exhibits 35% protein binding, meaning it can distribute into the tissues.4 In obese patients, this will decrease patient exposure to the drug, potentially decreasing efficacy. In fact, this has been corroborated in a subgroup analysis of the RE-LY trial, which showed a significant impact of weight on dabigatran plasma concentrations.40 Due to these data, the manufacturer states that those over 100 kg have about 20% lower trough concentrations compared to those between 50 and 100 kg.4 In addition, three case reports have been published in patients with a BMI of 40 kg/m2 or greater, each of which had thrombotic events while on therapy and/or had subtherapeutic concentrations of dabigatran.41-44

Practice Point

Though minimal data exist, the pharmacokinetic parameters and case reports suggest that weight or BMI may contribute to dabigatran failure, and should be avoided in this population.40-44

Rivaroxaban

Of the DOACs, rivaroxaban has the most favorable PK profile in patients with high body weight with a volume of distribution of 0.7 L/kg, protein binding of 92-95%.5 In alignment with this, a randomized, single-dose, placebo-controlled PK/PD study assessed rivaroxaban concentration in healthy patients of varying weights. Patients over 120 kg showed similar maximum concentrations, area under the curve, half-life, and inhibition of factor Xa activity, compared to those between 70 and 80 kg.45 Two large healthcare system databases looked at patients with Afib receiving warfarin or rivaroxaban and matched over 3,000 pairs of patients.46 Results determined a similar rate of stroke or SE and major bleeding in both treatment groups (stroke/SE: odds ratio [OR] 0.88, 95% CI 0.60-1.28; major bleeding: OR 0.80, 95% CI 0.59-1.08). In patients with VTE, a prospective cohort analysis evaluated patients with a variety of body weight categories (less than 50 kg, 50 to 120 kg, and greater than 120 kg) assessing drug levels and clinical outcomes which determined no difference in either outcome.47 A retrospective matched cohort study compared DOACs to warfarin in patients between 100 and 300 kg being treated for VTE.48 A majority of patients receiving a DOAC in this trial received rivaroxaban. The primary outcome, recurrence of VTE within 12 months of the index admission date showed no significant difference (6.5% vs 6.4%, p=0.93).48 Bleeding was also similar between the rivaroxaban and warfarin groups (1.7% vs 1.2%, p=0.31).48 A retrospective claims database study matched morbidly obese patients with VTE treated with rivaroxaban or warfarin (n=5,780).49 The rivaroxaban and warfarin treatment groups showed similar rates of recurrent VTE (OR 0.99, 95% CI 0.85-1.14) and major bleeding (OR 0.75, 95% CI 0.47-1.19).49

Practice Point

These studies demonstrate the probable safety and effectiveness of rivaroxaban in obesity for both Afib and VTE treatment.46-40

Apixaban

Apixaban has a moderate PK profile for maintaining concentrations in obese patients. It has a volume of distribution of 0.3-1.1 L/kg and 87% protein binding.6 A study assessing a single dose of apixaban was performed in healthy patients in a variety of weight categories.50 In those with a weight over 120 kg, the maximum concentration was 31% lower and the area under the curve was 23% lower compared to those between 65 and 85 kg.50 Furthermore, the volume of distribution was higher and half-life shorter. This suggests a lower exposure to the drug in patients with a higher body weight, though the clinical implications of this were not evaluated. A second PK/PD study was completed to assess anti-Xa levels in those with a high bodyweight, and determined that those over 120 kg had a reduction in concentration of the drug, and this demonstrated a correlation with anti-Xa levels (r=0.95, p<0.0001).51 Again, clinical consequences of this were not studied. The clinical impact of body weight on apixaban compared to warfarin was evaluated in a post-hoc analysis of the ARISTOTLE study.52 This determined no difference in efficacy between apixaban and warfarin in patients over 120 kg, but a lower risk of bleeding was maintained in the apixaban group.52

Practice Point

Collectively, these data suggest that apixaban exposure is lower in patients with high body weight, but this may not impact clinical outcomes, though the study populations were small so definite conclusions cannot be drawn.51,52

Edoxaban

Pharmacokinetic data for edoxaban are not ideal for obese patients with a volume of distribution of 1.5 L/kg and 55% protein binding.7 Despite this, the ENGAGE AF-TIMI 48 trial did assess the PK/PD outcomes and the relationship between BMI and clinical outcomes in patients receiving edoxaban for Afib.53 Interestingly, there were not different trough plasma concentrations or anti-Xa activity in different BMI groups or differences in clinical outcomes between edoxaban and warfarin.

Practice Point

Due to the non-favorable pharmacokinetic profile and the minimal data to support the use of edoxaban in patients with a high body weight, caution should be used if using edoxaban in this population.53

Summary of DOAC use in Obesity

Each DOAC has a variable response in patients who are obese based on the agent utilized. The clinical outcomes in this population largely reflect the PK profile of each agent, with rivaroxaban having the most favorable PK parameters and the most clinical data to support its use. The International Society of Thrombosis and Haemostasis (ISTH) endorses the use of rivaroxaban and apixaban for VTE treatment in patients with a BMI over 40 kg/m2 or a body weight of 120 kg or greater, recognizing most data fall with rivaroxaban.54 Recommendations are to avoid edoxaban and dabigatran in this population due to negative or lack of data.54 ISTH does not comment on Afib treatment, though if treating an obese patient with anticoagulation for Afib, it is reasonable to extrapolate the data from VTE treatment to suggest safety and effectiveness in this population as well.

Case 2

DW is a 48-year-old male (height: 5’10’’, weight: 142 kg, BMI: 44.9 kg/m2) who presents to the emergency department with pain, swelling and redness on his thigh. He recently traveled from the US to Asia and back for work. He is diagnosed with a new proximal DVT.

Medical History: Chronic pain

Medications: Gabapentin 300 mg three times daily

Pause and Reflect: What DOAC should be initiated for treatment of new VTE in DW?

Older Adults

Older adults have an increased risk of developing Afib requiring anticoagulation, but are also more likely to have bleeding events while receiving anticoagulation regardless of which anticoagulant they are receiving.55,56 This risk is reflected by the BEERS criteria, which includes both dabigatran and rivaroxaban as potentially inappropriate medications for adults 75 years and older due to an increased risk of gastrointestinal (GI) bleeding compared to warfarin.57 As patients age, they are also at an increased risk of renal function decline, which can change the exposure to DOACs. Dabigatran, rivaroxaban, apixaban, and edoxaban are all listed in the BEERs criteria as potentially requiring renal dose adjustments.

Dabigatran

In a post-hoc analysis of the RE-LY trial, assessing dabigatran versus warfarin in patients with Afib, the benefits of dabigatran compared to warfarin on stroke and rates of intracranial hemorrhage were maintained in all age groups.58 However, there was a significant interaction for extracranial major bleeding in patients 80 years of age and older. This showed a higher rate of extracranial hemorrhage for the 150 mg twice daily dose compared to warfarin (HR 1.68, 95% CI 1.18-2.41), and a similar rate for 110 mg twice daily (HR 1.50, 95% CI 1.03-2.18). In a post-hoc analysis of RECOVER and RECOVER-II assessing dabigatran compared to warfarin for VTE treatment, there was no difference in recurrent VTE or bleeding events in those 75 years or older between treatment groups, though only 288 patients were receiving dabigatran in this age group.22

Practice Point

These data support the use of dose adjusted dabigatran from 150 to 110 mg twice daily for Afib treatment in this population to decrease the risk of bleeding, though the common benefit of a decreased risk of intracranial hemorrhage with DOACs compared to warfarin is lost. Dabigatran may be an option for VTE treatment, but numbers were limited.22,58

Rivaroxaban

A post-hoc analysis of ROCKET-AF assessing rivaroxaban versus warfarin in patients with Afib, patients 75 years and older did have a higher rate of stroke and SE (2.57% vs 2.05%/100 patient-years; p=0.0068) as well as bleeding than younger patients (4.63% versus 2.74%/100 patient-years; p<0.0001).59 Treatment effect for stroke and SE or bleeding did not differ by age and treatment group (p interaction=0.336).59 Interestingly, in the original trial, patients receiving rivaroxaban had a lower rate of intracranial hemorrhage than warfarin, but this did not remain consistent when looking at patients 75 years and older (0.66/100 patient years with rivaroxaban vs 0.83/100 patient years with warfarin, p=0.3531). 59 Moreover, rates of GI bleeding were higher with rivaroxaban than warfarin in this age group (2.81/100 patient years vs. 1.66/100 patient years, p=0.0002).59 For VTE, a post-hoc analysis of EINSTEIN was completed which compared rivaroxaban to warfarin in patients over 75 years old.60 No difference was shown in the older population group for safety of efficacy, though only 440 patients were included in this age group.

Practice Point

For Afib, the potential safety risk suggests that rivaroxaban may not be the preferable DOAC in this population, and like dabigatran, the benefit of decreasing the risk of intracranial hemorrhage is lost.59 For VTE, rivaroxaban may be a viable option, but numbers are small in this analysis.60

Apixaban

In a post-hoc analysis of the ARISTOTLE study comparing apixaban to warfarin in 6,229 patients with Afib, rates of stroke and SE (HR 2.04, 1.59-2.61) and major bleeding (HR 3.13, 95% CI 2.56-3.83) were higher in patients over the age of 75 compared to younger than 65.61 For patients over the age of 75, apixaban had a lower risk of stroke or SE than warfarin (HR 0.71, 95% CI 0.53-0.95). Major bleeding was also lower in the apixaban group compared to warfarin (HR 0.64, 95% CI 0.52-0.79). Only 13% (n=2,436) of the population was over 80 years old, but in this group the results were consistent.61 Similarly, the AVERROES study assessing patients with Afib unsuitable for warfarin compared apixaban to aspirin.62 Those 75 years of age and older showed significantly decreased risk of stroke or systemic embolism, and similar rates of bleeding to aspirin, supporting use in this population.62 Furthermore, in a subgroup analysis of AMPLIFY, comparing apixaban to warfarin for VTE treatment, apixaban maintained efficacy and had a lower rate of bleeding in patients 75 years of age and older compared to warfarin.14

Practice Point

It appears apixaban maintains its effectiveness and safety profile in older adults, and is a reasonable treatment option for Afib and VTE in this population.14,61,62

Edoxaban

A post-hoc analysis of the ENGAGE-AF TIMI trial assessing edoxaban versus warfarin in patients with Afib, assessed the outcomes across three age groups (less than 65 years, 65-74 years, and 75 years and older).63 In patients 75 years of age and older, the rate of stroke or SE was similar between edoxaban and warfarin (HR 0.83, 95% CI 0.66-1.04).63 The rate of major bleeding was significantly decreased with edoxaban compared to warfarin (HR 0.83, 95% CI 0.70-0.99).63 The ELDERCARE-AF study assessed dose-adjusted edoxaban to placebo for Afib in Japanese patients 80 years of age or over. Edoxaban significantly reduced stroke incidence, but increased the risk of GI bleeding in this population.15 In a subgroup analysis of HOKUSAI-VTE comparing edoxaban to warfarin for VTE treatment, edoxaban maintained efficacy and safety outcomes in those 75 years of age and older.15

Practice Points

These results suggest edoxaban can potentially serve as a safer option than warfarin in patients 75 years of age or older for Afib and is a reasonable option for VTE.15,62 It is important to note that a dose reduction for this medication may be necessary, as patients with a CrCl between 15 and 50 mL/min should receive a dose adjustment from 60 mg to 30 mg daily.7 In the post-hoc analysis of ENGAGE-AF TIMI 48, more patients in the older age group did require a dose adjustment for renal function, supporting this consideration.63

All DOACs

For treatment of Afib, real world data retrospectively assessed DOACs in patients 75 years of age and older.64 Of the 142 patients included, the authors determined a rate of 1.37 bleeds per 100 person-years and determined DOACs appear to be a safe form of anticoagulation in this population.64 It is important to note that bleeding episodes were associated with a decline in GFR, and therefore renal function should be regularly assessed in this population. A prospective study was completed to compare warfarin to DOACs in patients 85 years of age and older for VTE treatment.65 Patients were included if they were enrolled in the survey on anticoagulated patients register.65 A total of 272 patients were included, and the study determined that bleeding rates and thrombotic events were higher in patients on DOACs (bleeding: HR 4.7, 95% CI 1.5-15.01; thrombotic events: HR 4.5, 95% CI 1.5-13.3) but a lower risk of mortality (HR 0.30, 95% CI 0.1-0.9).65 Results may have been influenced by patients past medical history as patients in the DOAC group were more likely to have a history of bleeding or thrombotic events before enrollment.65

Summary of DOACs for Older Adults

Based on data assessing DOAC use in older adults, caution should be used for dabigatran and rivaroxaban due to a potential for increased bleeding risk that aligns with the Beers criteria.57-59 Apixaban appears to be effective and potentially safer than warfarin in this population and edoxaban appears to be reasonable as well.61 Regardless of agent selected, decreased renal function may lead to an increased bleed risk in this population, and thus should be monitored frequently, particularly as it applies to dose adjustment requirements. Due to the ability to dose adjust apixaban as renal function declines, it may be pragmatic to use apixaban in this population recognizing the potential to need to dose reduce this medication as renal function and age change.

Case 3

BD is a 91-year-old woman (height: 5’1’’; weight: 49 kg; BMI: 19.5 kg/m2) who presents to the emergency department with new onset shortness of breath. She is diagnosed with atrial fibrillation.

Medical History: Hypertension, hyperlipidemia, heart failure with reduced ejection fraction, chronic kidney disease (SCr: 0.8 mg/dL, CrCl 35 mL/min)

Medications: Metoprolol succinate 50 mg daily, atorvastatin 40 mg daily, lisinopril 5 mg daily, spironolactone 12.5 mg daily, dapagliflozin 10 mg daily

Pause and Reflect: Which DOAC would pose the lowest bleed risk for BD?

Cancer

Cancer is a prothrombotic state, to which the degree of thrombosis development is dependent on the type and location of cancer. Low molecular weight heparin (LMWH) was traditionally the preferred agent over warfarin due to improved efficacy.66 Some of the DOACs have also been studied in this population to provide patients with an oral option if VTE treatment is warranted. Minimal data exist assessing DOAC use in a patient with concurrent cancer and Afib, but it may also be possible to use DOACs in this scenario.

Dabigatran

Treatment of cancer associated VTE with dabigatran has not been studied in a RCT and the evidence that does exist is limited to small subgroups or retrospective cohort studies. A post-hoc analysis of RE-LY in patients with Afib did determine that 44 of 546 major GI bleeds were associated with occult GI cancers, and most of these bleeds occurred in the dabigatran group.67

Practice Point

Based on limited information, dabigatran cannot be recommended in patients with cancer at this time.

Rivaroxaban

Rivaroxaban has been studied to treat cancer associated VTE in the SELECT-D trial.68 Patients were allocated to either rivaroxaban (n=203) or dalteparin (n=203) for treatment of new VTE, and those in the rivaroxaban group had a lower rate of 6-month VTE recurrence than the dalteparin group (HR 0.43, 95% CI 0.19-0.99).67 Major bleeding was not different between groups (HR 1.83, 95% CI 0.68-4.96), but rivaroxaban had higher rates of clinically relevant non-major bleeding (HR 3.76, 95% CI 1.63-8.69).67]

Practice Point

Due to the improved efficacy of rivaroxaban over dalteparin, rivaroxaban is an effective first line agent for cancer associated-VTE, but it is important to consider the potential for increased rates of clinically relevant non-major bleeding.68

Apixaban

Apixaban has been studied in two prospective randomized controlled trials in patients with cancer associated VTE.69,70 The Caravaggio study compared apixaban to dalteparin in 1,155 patients and found no difference in VTE rate (HR 0.63, 95% CI 0.37-1.07) or major bleeding at six months (HR 0.82, 95% CI 0.40-1.69).69 The ADAM-VTE trial similarly assessed 287 patients with cancer-associated VTE receiving apixaban or dalteparin and determined a low rate of ISTH major bleeding in both groups, 0% in the apixaban group and 1.4% (n=2) in the dalteparin group (p=0.138).70 Patients in the apixaban group had a lower rate of VTE than the dalteparin group (HR 0.099, 95% CI 0.013-0.78).70 Together these trials suggest that apixaban is at least as safe and effective as dalteparin, and may actually have superior outcomes, making this a reasonable option for patients with cancer associated VTE. Apixaban has also been evaluated in a post-hoc analysis of ARISTOTLE looking at those treated with apixaban for Afib and concomitant cancer (n=1,236), which demonstrated superior efficacy and safety of apixaban over warfarin.71

Practice Point

Due to the positive results of the collective data, apixaban is a reasonable option for VTE and Afib treatment in patients with cancer.69-71

Edoxaban

Edoxaban has been studied in a large RCT in patients with cancer associated VTE.72 Edoxaban was compared to dalteparin, and results showed that there was no difference in a composite of recurrent VTE or major bleeding (HR 0.97, 95% CI 0.70-1.36). When looking at each outcome individually, recurrent VTE was no different between edoxaban and dalteparin (HR 0.71, 95% CI 0.48-1.06), but there was an increase in major bleeding in those receiving edoxaban (HR 1.77, 95% CI 1.03-3.04).72 Edoxaban has also been evaluted for Afib treatment in patients with cancer in a post-hoc analysis of the ENGAGE-AF TIMI 48 trial.73 In this analysis, it was determined that 5.5% (n=1,153) of the total population had a malignancy, and in that population the efficacy and safety of edoxaban compared to warfarin is preserved.73

Practice Point

Edoxaban may be a potential treatment for VTE and an alternative to warfarin for Afib in patients with cancer.72,73

All DOACs

A few studies have been conducted that include an evaluation of a variety of DOACs in patients with cancer for either VTE or Afib. A meta-analysis assessing mainly edoxaban and rivaroxaban compared to LMWH for cancer-associated VTE found a lower risk of recurrent VTE within six months with the DOACs (RR 0.65, 95% CI 0.42-1.01), but a higher rate of major bleeding (RR 1.74, 95% CI 1.05-2.88) compared to LMWH.74 A study completed using the MarketScan database looked at over 16,000 patients with cancer and Afib treated with dabigatran, rivaroxaban, apixaban, or warfarin.75 Rates of stroke were similar in those receiving DOACs and warfarin.75 Compared to warfarin, dabigatran and rivaroxaban had similar rates of bleeding (dabigatran: HR 0.96, 95% CI 0.72-1.27; rivaroxaban: HR 1.09, 95% CI 0.79-1.39) and apixaban had lower rates of bleeding (HR 0.37, 95% CI 0.17-0.79).75 These results align with the above drug-specific investigation into DOAC use in patients with cancer.

Summary of DOAC use in Cancer

Several guidelines are available to help in selection of anticoagulants to be used for cancer associated VTE (see Resources). The American Society of Clinical Oncology recommends initial anticoagulation with LMWH, unfractionated heparin (UFH), fondaparinux, or rivaroxaban after development of a VTE, and long-term anticoagulation (at least 6 months) with LMWH, edoxaban, or rivaroxaban.76 Of note, one large RCT assessing apixaban in this population was published after the guidelines were released, which may have impacted its exclusion from the guidelines.69 The American Society of Hematology suggests apixaban or rivaroxaban, and recommends LMWH or UFH for initial anticoagulation, and suggests treatment for 3-6 months with apixaban, edoxaban, or rivaroxaban over LWMH or warfarin.77 These guidelines were published in 2021, and did incorporate the more recent data with apixaban. In both cases, the guidelines remind providers of the high bleeding risk of certain types of cancers (i.e., GI) and that some studies with the DOACs did show in increased risk of GI bleeding, and this should be considered when selecting and agent to be used.

Case 4

KR is a 37-year-old individual with colorectal cancer status-post resection. They present to their oncologist complaining of new shortness of breath. After further work-up KR is determined to have a new pulmonary embolism.

Medical History: colorectal cancer (active), hypothyroidism

Medications: Oxaliplatin 85 mg/m2 every two weeks, levothyroxine 25 mcg once daily

Pause and Reflect: Which DOAC would be most optimal to treat KR’s new PE?

Hypercoagulable States

Hypercoagulable states pose a challenge for anticoagulant choice, as despite the anticoagulant chosen, patients may still be at high risk for development of additional thromboembolic events. Furthermore, hypercoagulable states vary in severities and may respond differently to anticoagulants. Finally, hypercoagulable states cannot all be tested for at the time of a thrombotic event, so this information is not always known to the provider when selection of an anticoagulant occurs.

Antiphospholipid Syndrome

Antiphospholipid syndrome is defined by the Sapporo-Sydney criteria which requires a clinical criteria (thrombosis or obstetrical morbidity) as well as the presence of one or more positive antiphospholipid antibodies including lupus anticoagulant, immunoglobulin (Ig)G or IgM cardiolipin antibodies, and IgG or IgM anti-beta-2 glycoprotein-I.78 The more positive antibodies a patient has, the more likely the patient is to develop a thrombotic event, with triple positivity having the highest risk at over 5 events per 100 patient years.79 Due to the variability in this syndrome, patients may require different treatment approaches. In patients with triple positivity, rivaroxaban has been shown to be inferior to warfarin in the Rivaroxaban in Thrombotic Antiphospholipid Syndrome (TRAPs) trial, which ended early due to poor outcomes in the rivaroxaban group.80 A second prospective randomized trial showed that in patients with any type of antiphospholipid syndrome, rivaroxaban did not meet the noninferiority margin, and when looking at the data, had almost double the thrombotic events as warfarin.81 It is important to note that almost all thrombotic events occurred in those with triple positivity (n=15/17), so it is difficult to determine if these data can be applied to other types of antiphospholipid syndrome.81 A systematic review assessed rates of thrombotic events in patients with antiphospholipid syndrome receiving DOACs.81 In follow-up of just over a year, the recurrent VTE rate was 16%, with an over four-fold increase in events in patients who were triple positive (OR 4.3, 95% CI 2.3–7.7).82

Practice Point

Collectively these data support avoidance of DOACs in patients with triple positive antiphospholipid syndrome, but provide little guidance for those with other types of antiphospholipid syndrome.81,82

The ASTRO-APS trial comparing apixaban to warfarin in patients with antiphospholipid syndrome is estimated to be completed this year, and the RISAPS trial comparing rivaroxaban to warfarin in this population is anticipated to be completed in 2022, hopefully shedding more light on this subject.

Hereditary Thrombophilia

Due to genetic mutations in the coagulation system, patients may be at an increased risk of developing VTE.83 A variety of mutations exist, most commonly loss-of-function of natural anticoagulants (protein C/S, antithrombin) or gain-of-function in procoagulant proteins (factor V Leiden [FVL]). Loss-of-function mutations are most detrimental with a 10-30-fold relative increase in initial VTE compared to those without the condition. Very few data evaluating anticoagulation exist in these populations, and most data look at any patient with hereditary thrombophilia without separating patients based on their specific mutation.84-90 A retrospective claims-based study assessed the MarketScan database in patients with a new VTE and antiphospholipid syndrome (APS), protein C or S deficiency, prothrombin gene mutation, and lupus anticoagulant receiving rivaroxaban or warfarin (n=806).89 In those receiving rivaroxaban, 3% of patients developed a recurrent VTE and 4.2% of those receiving warfarin (p=0.34) and bleeding was similar between groups. A systematic review of patients in the landmark trials with hereditary thrombophilia or APS compared DOACs to warfarin.90 This determined no difference in recurrent VTE (RR 0.7, 95% CI 0.34-1.44) or bleeding (RR 0.92, 95% CI 0.62-1.36).90 Both studies had low numbers of patients with higher risk gene mutations (loss-of-function), making results difficult to extrapolate to this population.

Practice Point

In those with lower risk mutations, it appears to be reasonable to use DOACs for treatment, though data are limited.83-90

Case 5

MT is a 58-year-old woman who has a FVL hypercoagulable state. She presents to her primary care clinician with new onset swelling and redness in her calf and thigh. MT is frustrated because she has developed VTEs on warfarin in the past and wonders if there are any alternatives.

Medical History: Factor V Leiden, multiple VTEs

Medications: Warfarin (INR goal 2-3, 2.7 today)

Pause and Reflect: Is a DOAC a reasonable alternative for MT? If so, which DOAC would you suggest?

Pharmacist's Role

Pharmacists can play an important role in recommending DOAC selection or avoidance of DOACs in high-risk populations. Clearly, data vary across subgroups, and a one-size-fits-all approach is not appropriate. Using the data included in this CE activity, pharmacists should be able to play a more active role as a member of the care team with regard to making recommendations regarding an optimal treatment option for patients with renal dysfunction, obesity, cancer, hypercoagulable states, and older adults. Pharmacists should also recognize the limitations in the evidence we do have for these populations, and be advocates on their teams for agent selection being a shared decision between the healthcare team and patient.

Audio: What is the pharmacist’s role in designing anticoagulation regimens for transitions between anticoagulants and for use in combinations with other interacting medications?

Audio: What is the pharmacist’s role in formulating patient education interventions for high-risk patients?

Resources

Cardiology

Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report – Executive Summary. Available at https://journal.chestnet.org/article/S0012-3692(21)01507-5/fulltext

Chen A, Stecker E, Warden BA. Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges. J Am Heart Assoc. 2020;9:e017559. Available at https://www.ahajournals.org/doi/epub/10.1161/JAHA.120.017559

January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 Guideline for Management of Patients with Atrial Fibrillation. 10.1016/j.jacc.2019.01.011. Available at https://www.acc.org/~/media/Non-Clinical/Files-PDFs-Excel-MS-Word-etc/Guidelines/2019/2019-Afib-Guidelines-Made-Simple-Tool.pdf

Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-352. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7. Erratum in: Chest. 2016;150(4):988

Kumbhani DJ, Cannon CP, Beavers CJ, et al. 2020 ACC Expert Consensus Decision Pathway for Anticoagulant and Antiplatelet Therapy in Patients With Atrial Fibrillation or Venous Thromboembolism Undergoing Percutaneous Coronary Intervention or With Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2020;Dec 18:[Epub ahead of print]. Available at https://reader.elsevier.com/reader/sd/pii/S0735109720366158?token=C8A231C315B186FFDC3814BC57A9AD6D9968A37F5DED0776EA6F4B4854265136B2D86A756C8DD925CE5AAD3BA6C07897&originRegion=us-east-1&originCreation=20210826165507

Obesity

Martin KA, Beyer-Westendorf J, Davidson BL, et al. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost. 2021;19(8):1874-1882. doi: 10.1111/jth.15358. Epub 2021 Jul 14. Available at https://onlinelibrary.wiley.com/doi/10.1111/jth.15358.

Oncology

Key NS, Khorana AA, Kuderer NM, et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2020;38:5:496-520.

Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 Guidelines for Management of Venous Thromboembolism: Treatment of Deep Vein Thrombosis and Pulmonary Embolism. Blood Adv. 2020; 4 (19): 4693–4738. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556153/

Primary Care

Wigle P, Hein B, Bernheisel. Anticoagulation: Updated Guidelines for Outpatient Management. Am Fam Physician. 2019 Oct 1;100(7):426-434. Available at https://www.aafp.org/afp/2019/1001/p426.html

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